The molecular chaperone HSP60 is a chaperonin homolog of GroEL. We had previously shown that the immunosuppressant mizoribine is bound directly to HSP60 and inhibited its chaperone activity. However, the inhibitory me...The molecular chaperone HSP60 is a chaperonin homolog of GroEL. We had previously shown that the immunosuppressant mizoribine is bound directly to HSP60 and inhibited its chaperone activity. However, the inhibitory mechanisms of HSP60 by mizoribine have not yet been fully understood. In the present study, we investigated the influence of mizoribine on a folding cycle of HSP60 and co-chaperone HSP10. Our results showed that mizoribine inhibited the folding cycle of HSP60/HSP10. The ATPase activity of HSP60/HSP10 was decreased in the presence of mizoribine and the dissociation of HSP10 from HSP-60 was also decreased by mizoribine. The same functions of GroEL and/or GroES were slightly affected by mizoribine. Based on our findings, we discuss the inhibitory mechanisms of HSP60 by mizoribine.展开更多
Background Mizoribine (MZR) is an immunosuppressant used to treat adult nephropathy.There is little experience with the drug in treating Chinese children with frequently relapsing nephrotic syndrome (FRNS).We investig...Background Mizoribine (MZR) is an immunosuppressant used to treat adult nephropathy.There is little experience with the drug in treating Chinese children with frequently relapsing nephrotic syndrome (FRNS).We investigated the efficacy and safety for treating MZR with FRNS.Furthermore,the relationship between efficacy and serum concentration was investigated.Methods A prospective multicenter observational 12-month study was performed for evaluating the usefulness of MZR with FRNS.Serum MZR concentration was measured,and the relationships between pharmacokinetic parameters (Cmax,AUC),number of relapses,and urinary protein were evaluated.Results Eighty-two pediatric patients from four hospitals were treated with MZR and prednisone.MZR treatment significantly reduced the number of relapses and steroid doses.A correlation between pharmacokinetic parameters and relapses was observed,which fits well with the sigmoidal Emax model.Even in the relationship between pharmacokinetic parameters and urinary proteins,it was recognized that there was a threshold in the pharmacokinetic parameters for the therapeutic effect similar to the results obtained with the sigmoidal Emax model.Eleven patients (13.4%) experienced mild adverse events.Conclusions MZR therapy was effective in reducing the number of relapses and steroid doses.No severe adverse reactions were observed.Therapeutically effective serum concentrations were estimated to be Cmax > about 2 μg/mL or AUC > about 10 lag h/mL.MZR and steroid treatment were effective and safe for pediatric FRNS.展开更多
Background Lupus nephritis （LN） is one of the most serious manifestations of systemic lupus erythematosus.Although there have been substantial improvements in LN treatment over the last decade,the outcome remains un...Background Lupus nephritis （LN） is one of the most serious manifestations of systemic lupus erythematosus.Although there have been substantial improvements in LN treatment over the last decade,the outcome remains unoptimistic in a considerable percentage of patients.The aim of this study was to evaluate the efficacy and safety of mizoribine （MZR）,a novel selective inhibitor of inosine monophosphate dehydrogenase,as induction treatment for active LN in comparison with mycophenolate mofetil （MMF） and intravenous cyclophosphamide （CYC）.Methods Ninety patients with active LN were observed.Thirty patients were given MZR orally at the dose of 300 mg every other day.Thirty patients took MMF at 2 g per day in two divided doses.Thirty patients received CYC intravenously 0.5 g every 2 weeks.Therapeutic effects and adverse events （AEs） were evaluated at the end of 24-week treatment.Oneway analysis of variance （ANOVA） followed by Dunn＇s test was applied to compare the difference among the groups.For comparing categorical data between two groups,χ^2 test was employed.Results Early responses at week 12 were achieved by 73.3%,90.0%,and 96.7% in MZR,MMF,and CYC groups,respectively.There was no significant difference in the complete remission rates （22.7%,24.0%,and 25.0%,respectively） or overall response rates （68.2%,72.0%,and 75.0%,respectively） among the three groups at week 24.The most prominent drop-down of Systemic Lupus Erythematosus Disease Activity Index scores was observed in MMF or CYC group,and the decline of health assessment questionnaire scores in MZR or MMF group was more prominent than that in the CYC group at week 12.Serum complement 3 （C3） or C4 levels were elevated in all groups after the treatments.CYC was more effective in inhibiting anti-double-stranded DNA antibody,while MZR was more effective in inhibiting antinuclear antibody.The incidences of AEs in patients treated with CYC were significantly higher than those in patients treated with MZR or MMF （24.2% for CYC vs.3.3% for MZR,and 2.6% for MMF,P=0.01）.Conclusions MZR is well tolerated and has an effect similar to MMF in the induction therapy of active LN.MZR may serve as an alternative approach for LN patients.展开更多
Background:Mizoribine(MZR)is a selective inhibitor of inosine monophosphate dehydrogenase,a key enzyme in the pathway responsible for de novo synthesis of guanine nucleotides.As an immunosuppressant,MZR has been used ...Background:Mizoribine(MZR)is a selective inhibitor of inosine monophosphate dehydrogenase,a key enzyme in the pathway responsible for de novo synthesis of guanine nucleotides.As an immunosuppressant,MZR has been used successfully without any serious adverse effects in the treatment of renal diseases in children as well as adults.Besides its immunosuppressive effect,MZR has been reported to ameliorate tubulointerstitial fibrosis in rats via suppression of macrophage infiltration.Data Sources:In this review,we summarize reported possible benefits of MZR in the treatment of pediatric-onset glomerular disease.Results:We recently observed that MZR itself selectively attenuates the expression of monocyte chemoattractant protein-1 at both the mRNA and protein levels in human mesangial cells.Since MZR binds specifically to 14-3-3 proteins and heat shock protein 60,both of which are reportedly expressed in inflamed glomeruli,MZR may bind directly to inflamed glomerular cells,thereby possibly preventing progressive damage from glomerulonephritis through a suppressive effect on activated macrophages and intrinsic renal cells.Moreover,it has recently been reported that MZR directly prevents podocyte injury through correction of the intracellular energy balance and nephrin biogenesis in cultured podocyte and rat models,suggesting a direct anti-proteinuric effect of MZR.Conclusions:These beneficial mechanisms of action of MZR as well as its immunosuppressive effect would warrant its use in the treatment of pediatric-onset glomerular disease.Although further studies remain to be done,we believe that MZR may be an attractive treatment of choice for children with glomerular diseases from a histologic as well as clinical standpoint.展开更多
文摘The molecular chaperone HSP60 is a chaperonin homolog of GroEL. We had previously shown that the immunosuppressant mizoribine is bound directly to HSP60 and inhibited its chaperone activity. However, the inhibitory mechanisms of HSP60 by mizoribine have not yet been fully understood. In the present study, we investigated the influence of mizoribine on a folding cycle of HSP60 and co-chaperone HSP10. Our results showed that mizoribine inhibited the folding cycle of HSP60/HSP10. The ATPase activity of HSP60/HSP10 was decreased in the presence of mizoribine and the dissociation of HSP10 from HSP-60 was also decreased by mizoribine. The same functions of GroEL and/or GroES were slightly affected by mizoribine. Based on our findings, we discuss the inhibitory mechanisms of HSP60 by mizoribine.
文摘Background Mizoribine (MZR) is an immunosuppressant used to treat adult nephropathy.There is little experience with the drug in treating Chinese children with frequently relapsing nephrotic syndrome (FRNS).We investigated the efficacy and safety for treating MZR with FRNS.Furthermore,the relationship between efficacy and serum concentration was investigated.Methods A prospective multicenter observational 12-month study was performed for evaluating the usefulness of MZR with FRNS.Serum MZR concentration was measured,and the relationships between pharmacokinetic parameters (Cmax,AUC),number of relapses,and urinary protein were evaluated.Results Eighty-two pediatric patients from four hospitals were treated with MZR and prednisone.MZR treatment significantly reduced the number of relapses and steroid doses.A correlation between pharmacokinetic parameters and relapses was observed,which fits well with the sigmoidal Emax model.Even in the relationship between pharmacokinetic parameters and urinary proteins,it was recognized that there was a threshold in the pharmacokinetic parameters for the therapeutic effect similar to the results obtained with the sigmoidal Emax model.Eleven patients (13.4%) experienced mild adverse events.Conclusions MZR therapy was effective in reducing the number of relapses and steroid doses.No severe adverse reactions were observed.Therapeutically effective serum concentrations were estimated to be Cmax > about 2 μg/mL or AUC > about 10 lag h/mL.MZR and steroid treatment were effective and safe for pediatric FRNS.
文摘Background Lupus nephritis （LN） is one of the most serious manifestations of systemic lupus erythematosus.Although there have been substantial improvements in LN treatment over the last decade,the outcome remains unoptimistic in a considerable percentage of patients.The aim of this study was to evaluate the efficacy and safety of mizoribine （MZR）,a novel selective inhibitor of inosine monophosphate dehydrogenase,as induction treatment for active LN in comparison with mycophenolate mofetil （MMF） and intravenous cyclophosphamide （CYC）.Methods Ninety patients with active LN were observed.Thirty patients were given MZR orally at the dose of 300 mg every other day.Thirty patients took MMF at 2 g per day in two divided doses.Thirty patients received CYC intravenously 0.5 g every 2 weeks.Therapeutic effects and adverse events （AEs） were evaluated at the end of 24-week treatment.Oneway analysis of variance （ANOVA） followed by Dunn＇s test was applied to compare the difference among the groups.For comparing categorical data between two groups,χ^2 test was employed.Results Early responses at week 12 were achieved by 73.3%,90.0%,and 96.7% in MZR,MMF,and CYC groups,respectively.There was no significant difference in the complete remission rates （22.7%,24.0%,and 25.0%,respectively） or overall response rates （68.2%,72.0%,and 75.0%,respectively） among the three groups at week 24.The most prominent drop-down of Systemic Lupus Erythematosus Disease Activity Index scores was observed in MMF or CYC group,and the decline of health assessment questionnaire scores in MZR or MMF group was more prominent than that in the CYC group at week 12.Serum complement 3 （C3） or C4 levels were elevated in all groups after the treatments.CYC was more effective in inhibiting anti-double-stranded DNA antibody,while MZR was more effective in inhibiting antinuclear antibody.The incidences of AEs in patients treated with CYC were significantly higher than those in patients treated with MZR or MMF （24.2% for CYC vs.3.3% for MZR,and 2.6% for MMF,P=0.01）.Conclusions MZR is well tolerated and has an effect similar to MMF in the induction therapy of active LN.MZR may serve as an alternative approach for LN patients.
基金supported by grants-in-aid for Science from the Ministry of Education,Culture,Sports,Science and Technology of Japan(TH and IT).
文摘Background:Mizoribine(MZR)is a selective inhibitor of inosine monophosphate dehydrogenase,a key enzyme in the pathway responsible for de novo synthesis of guanine nucleotides.As an immunosuppressant,MZR has been used successfully without any serious adverse effects in the treatment of renal diseases in children as well as adults.Besides its immunosuppressive effect,MZR has been reported to ameliorate tubulointerstitial fibrosis in rats via suppression of macrophage infiltration.Data Sources:In this review,we summarize reported possible benefits of MZR in the treatment of pediatric-onset glomerular disease.Results:We recently observed that MZR itself selectively attenuates the expression of monocyte chemoattractant protein-1 at both the mRNA and protein levels in human mesangial cells.Since MZR binds specifically to 14-3-3 proteins and heat shock protein 60,both of which are reportedly expressed in inflamed glomeruli,MZR may bind directly to inflamed glomerular cells,thereby possibly preventing progressive damage from glomerulonephritis through a suppressive effect on activated macrophages and intrinsic renal cells.Moreover,it has recently been reported that MZR directly prevents podocyte injury through correction of the intracellular energy balance and nephrin biogenesis in cultured podocyte and rat models,suggesting a direct anti-proteinuric effect of MZR.Conclusions:These beneficial mechanisms of action of MZR as well as its immunosuppressive effect would warrant its use in the treatment of pediatric-onset glomerular disease.Although further studies remain to be done,we believe that MZR may be an attractive treatment of choice for children with glomerular diseases from a histologic as well as clinical standpoint.
